Processes for the production of salts of beta-methyl choline and acyl derivatives thereof



Patented Mar. 1940 UNIT-ED sTATEs *IPATEN oi-Flo s PROCESSES FOR THEPRODUCTION OF SALTS 0F ,B-METHYL CHOLINE AND ACYL DERIVATIVES THEREOFGeorg Roeder, Rahway,'N. J., assignor to Merck Co. vInc., Rahwa'y, N. Lacorporation of .New

-. J ersey,

No Drawing.

8 Claims.

advantages which detract from its suitability for the production ofB-methyl choline salts and their derivatives on a commercial scale. Theprocess described by Morley requires the use of autoclaves, fortechnical reasons and, furthermore, it is doubtful if the pure B-isomercan be obtained by this process without further purification.

On the other hand, the halogenated acetones employed as startingmaterialsin the Major and Cline process are not readily availablecommercial products and great precaution must be taken in. theirmanufacture, because of the pronounced irritating properties which theyexhibit.

In an application being filed concurrently herewith, I have described animproved process by which these salts and/ or their acyl derivatives maybe prepared directly in substantial yield.- That process involvesreaction between propylene oxide and trimethylamine, followed byneutralization with the appropriate acid and, if desired,

subsequent acylation.

However, it sometimes happens that the ester of an acid are more readilyavailable than the acid itself. The present invention, therefore, is 40more particularly concerned with a process for producing these acylatedsalts of p-methyl choline in which the acid esters may be employed. Sucha process is particularly desirable in the :case of the alkyl-sulfuric'acids, for example. Theesters of these acids are more readily availablesubstances than the acids themselves, and in addition, the acidcomponent of methyl choline methosulfatewould not be stable if itsaqueous solution were evaporated, as is required in my otherabove-described process.

Generally speaking, my new process comprises acylating l-dimethylamino 2hydro-xypropane, and then treating the resulting acyl ester withalkylating agents.

In this way, I have prepared acetyl-s-methyl' is allowed to stand forseveral hours at room Applicationlanuary 30, 1937, Serial No. 123,153

choline methylsulfate, which would be difficult to prepare by otherknown processes. This acylated salt of s-methyl choline has considerabletechnical importance because of its slight hygroscopicity as comparedwith other derivatives of acetyl- B-methyl choline.

In the following example, I am illustrating a preferred embodiment of myinvention which is described by way of illustration and not of limimtation, and which may obviously be modified in certain respects withoutdeparting from the spirit and scope of my invention.

Eatample About 100 gms. of l-dimethylamino-Z-hydroxypropane are droppedinto about 200 gms. of boiling acetic anhydride, and refluxed for abouttwo hours. The solution is allowed to stand for about 10 hoursQafterwhich time it is shaken to dryness in vacuo. The residue is dissolved inacetic anhydride and then mixed with the calculated quantity ofdimethylsulfate. The temperature of the mixture rises spontaneously andit may be necessary to'cool the mixture. It

temperature. Ethyl acetate or ether is added to the cold solution andthe precipitated acetyl- B-methyl choline methyl sulfate is purified bydissolving it in acetic anhydride and again precipitating with ether orethyl acetate. It occurs in the form of thin prismatic plates having amelting point of about C.

For dimethylsulfate, other alkylating agents containing amethyl radicalmaybe substituted. Thus, following the esterification of the'l-dimethylamino 2 hydroxypropane with boiling acetic anhydride, themixture may be cooled, the calculated amount of methyl bromide added,and the mixture allowed to stand for about 10 hours. The product isisolated and purified in accordance with the further steps describedabove in connection with the production of the methylsulfate.

I claim as my invention: 5

1. A process for the production of acylated 4 B-methyl choline saltswhich comprises'reacting l-dimethylamino-2-hydroxypropane with analiphatic acid anhydride, and treating the resulting acyl ester thusobtained with alkylating agents. 50

2. A process for the production of acetyl-B- methyl-cholinemethylsulfate which comprises reacting 1 dimethylamino 2 hydroxypropanewith acetic anhydride, and treating the resulting acyl ester withdimethylsulfate.

3. AcetyleB-methyl-choline methylsulfate.

4. A process for the production of acetyl-pmethyl-choline-methy1sulfatewhich comprises 5. A process for the production of acetyl-flymethyl-oholine-bromide which comprises react-.

ing 1 dimethy1amino-2-hydroxypropane with boiling acetic anhydride,mixing the solution with methylbromide, adding ethyl acetate, andpurify-' ing the precipitated acetyl-fi-methyl-choline bromide bydissolving in acetic anhydride and precipitating.

6. A process for the production of acetyl-#- methyl-choline chloridewhich comprises reacting- With an alkylating agent.

1-dimthylamino-Z-hydro2ypropane with boiling acetic anhydride, treatingthe solution with methylchloride, adding ethyl acetate, and purifyingthe precipitated acetyl-fi-methyl-choline chloride by dissolving inacetic anhydride and precipitating.

7 A process for the production of acylatedj p-methyl choline salts whichcomprises acylating 1-dimethylamino-2-hydroxypropane, withan aliphaticacid anhydride, and treating the resulting acyl ester with an'alkylating agent. v

8. A processvfor the production of acylatedfi-methyl choline salts whichcomprises reacting 1-dimethy1amino-2-hydroxypropane with aceticanhydride, and treating the resulting acetyl ester v(mono ROEDER;

